Project Summary: This application seeks to support the career development of Dr John H. Stewart, IV. His long-term goal is to attain the necessary skills to become a well-trained clinician-scientist with a focus in the treatment of metastatic colorectal cancer and eventually become competitive for independent funding support. This goal will be met by a structured career development plan as well as a well-designed research project. Dr. Stewart's career development strategy will involve continued engagement with his present mentoring committee and participation in a structured didactic course of study to fill gaps in his scientific background. Dr. Stewart will present his research findings at national meetings and publish his work in peer reviewed journals during the proposed career development period. In addition to the aforementioned career development plan, Dr. Stewart and his mentoring committee have devised a research project titled Oncolytic Vesicular Stomatitis Virus (VSV) for the Treatment of Colorectal Cancer. The overall hypothesis of this research project is that local delivery of oncolytic VSV can effectively treat properly selected, metastatic colorectal tumors of the liver and peritoneum. This hypothesis will be tested by three specific aims. In Specific Aim 1, he will seek to identify the molecular determinants of host-cell permissiveness to VSV in colorectal cancer cells. In Specific Aim 2 he will define the apoptotic pathways activated by VSV in colorectal cancer cells. In Specific Aim 3 he will delineate the efficacy of loco-regional delivery of VSV in small animal models of metastatic colorectal cancer. The research proposed in this application will set the stage for further translational research by advancing the novel paradigm of local delivery of oncolytic VSV for the treatment of metastatic colorectal cancer. The Comprehensive Cancer Center of Wake Forest University provides an excellent environment for a mentored training program. This center incorporates expertise from a broad variety of disciplines and has extensive resources. Dr. Stewart has laboratory space that is fully funded by the Department of Surgery. He has the full support of his Division Chief to devote at least 75% of his time to the career development plan outlined in this proposal. Relevance: It is projected that 153,760 individuals will be diagnosed with colorectal cancer in 2007. Despite advances in early diagnosis, surgery and systemic therapy, an estimated 52,180 patients will die of metastatic disease this year. Clearly, new therapies are needed to treat advanced colorectal cancer. This project will attempt to address the need for novel treatments of metastatic colorectal cancer by exploring the efficacy of VSV in the treatment of this disease.